Peripheral neuropathies are a heterogeneous group of diseases that cause pathologic degeneration of the peripheral nervous system, and may involve motor, sensory and autonomic fiber types. Damage to peripheral nerves has several etiologies, including systemic disease such as diabetes and hypothyroidism, toxin exposures, nutritional deficiencies, infections and hereditary disorders. Neuropathy is also a feature of the aging process.
The most common inherited peripheral neuropathy in humans, Charcot-Marie-Tooth (CMT) disease, causes progressive deterioration of motor and sensory nerves, muscular atrophy, and chronic pain. About 1 in 2,500 individuals are affected by CMT. Current treatments for CMT manage symptoms rather than modify the disease course. CMT results in axonal degeneration in nerves with long axons, such that the neuropathy is generally more pronounced distally. Differentiation of various neuropathies is dependent on patient history, exclusion of metabolic disease, electro-diagnostics and genetic testing. In humans, CMT variants include CMT type 1 (CMT1) and CMT type 2 (CMT2). CMT1 variants are de- or dysmyelinating, while CMT2 variants are axonal neuropathies. In humans, over 80 causative genetic variants associate with CMT, although the genetic cause for many cases remains unknown. CMT1 is associated with mutations in genes that encode proteins influencing Schwann cell function and myelination. CMT2-associated genes are associated with critical axonal processes such as mitochondrial dynamics.
Idiopathic acquired laryngeal paralysis in the dog was first identified in the mid-1950s. (O'Brien J A, Harvey C E, Kelly A M, Tucker J A. Neurogenic atrophy of the laryngeal muscles of the dog. J Small Anim Pract 1973; 14(9):521-32.) Today it is a well-recognized specific clinical syndrome confirmed as a generalized acquired peripheral neuropathy (APN) condition with high prevalence in specific dog breeds. Clinically and diagnostically, APN resembles human CMT disease with associated alterations in electro-diagnostic profiles and pathologic changes to peripheral nerves. Although rare, CMT disease symptoms in humans can include laryngeal paralysis. Many canine diseases are caused by mutations in the same genes that produce corresponding disease in humans, including complex traits, such as hip dysplasia, and monogenic traits, such as muscular dystrophy.
Thus, for example, a major barrier to rapid progress in the development of disease-modifying medical treatment for human patients affected with peripheral neuropathy is a lack of understanding of the genetic basis of the disease and the lack of suitable large animal models. Continued existence of this barrier represents an important problem because, currently, therapies for patients with peripheral neuropathy and other types of motor neuron disease such as amyotrophic lateral sclerosis (ALS) and CMT are entirely symptomatic and do not modify or reverse progression of the disease over time.
In certain dog breeds, acquired peripheral neuropathy (APN) syndrome is common. Labrador Retrievers represent >70% of APN cases, although other breeds can also be affected, particularly Golden Retrievers, Poodles, and Irish Setters. It is estimated that as many as 50-75% of Labrador Retrievers get APN when over 12 years of age. The Labrador Retriever is the most common dog breed in the USA. Affected dogs have often been used for breeding before clinical signs develop. There is currently no disease modifying therapy available for dogs with APN. Moreover, presentation of APN in the dog is similar to both ALS and CMT diseases in humans. Humans with CMT can develop upper airway disorders, and fast-course ALS patients may present with laryngeal paralysis. Thus, there is a long-felt and unmet need for a diagnostic test that predicts the likelihood that a mammalian subject will exhibit, as some point in its life, an acquired peripheral neuropathy.